Modulation of Odorant Receptor Function

描述(申请人提供)：哺乳动物的气味感知是一个复杂的过程，由G蛋白偶联受体(GPCRs)家族介导，G蛋白偶联受体(GPCRs)被称为气味受体(ORs)，表达在数百万排列在嗅觉上皮细胞内的嗅觉神经元(OSN)的纤毛上。嗅觉上皮受自主神经的丰富支配， 包括释放乙酰胆碱的副交感神经末梢。我们最近发现OSN表达3型M胆碱受体(M3R)，另一种GPCR。然而，OSNs胆碱能作用的分子机制还不是很清楚。我们建议进行实验，以解决嗅觉调节的重要性，并阐明乙酰胆碱受体对OSN信号的影响的分子机制。这项工作将进一步加深我们对信息处理是如何在嗅觉的最早阶段发生的理解。为了验证M3R对OR功能和嗅觉信号转导起重要作用的假说，我们提出了以下具体目标：目的1.验证M3R调节嗅觉感觉神经元功能的假说；目的2.验证M3R参与气味介导的替代信号激活的假说；3.确定M3R的结构域以及对M3R和OR功能相互作用重要的信号成分。这些研究与健康相关的是，更好地理解ORS的调节机制和下游信号转导将有助于深入了解GPCRs信号的一般特征，GPCRs是心脏、精神和癌症疾病最常见的药物靶点。这项工作将促进我们对G蛋白偶联ORs如何受到另一种GPCR M3R的调节的理解，M3R是由副交感神经系统的关键神经递质乙酰胆碱激活的。了解神经递质受体和外周嗅觉系统之间的相互作用提供了重要的信息，可能有助于为嗅觉受损的无嗅觉和低血糖患者提供新的治疗方法，并减少与气味相关的压力，提高他们的生活质量。 公共卫生相关性：这些研究的健康相关性是，更好地了解ORS的调节机制和下游信号转导将提供对GPCRs信号的一般特征的洞察，GPCRs是心脏、精神和癌症疾病最常见的药物靶点。这项工作将促进我们对G蛋白偶联ORs如何受到另一种GPCR M3-R的调节的理解，M3-R是由副交感神经系统的关键神经递质乙酰胆碱激活的。了解神经递质受体和外周嗅觉系统之间的相互作用提供了重要的信息，可能有助于为嗅觉受损的无嗅觉和低血糖患者提供新的治疗方法，并减少与气味相关的压力，提高他们的生活质量。

DESCRIPTION (provided by applicant): Odor perception in mammals is a complex process mediated by the activation of a family of G- protein coupled receptors (GPCRs) known as odorant receptors (ORs) expressed at the cilia of millions of olfactory sensory neurons (OSNs) lining the olfactory epithelium. The olfactory epithelium is richly innervated by autonomic nerves, including parasympathetic nerve endings which release acetylcholine. We recently discovered that OSNs express the type 3 muscarinic acetylcholine receptor (M3R), another GPCR. However, the molecular mechanisms underlying cholinergic actions on OSNs are not well-understood. We propose experiments to address the importance of modulation of olfaction and to clarify the molecular mechanisms that underlie the effects of acetylcholine receptors on OSN signaling. This work will further our understanding of how information processing occurs during the earliest steps of olfaction. To test the hypothesis that the M3R is important for the regulatio of OR function and olfactory signal transduction, the following Specific Aims are proposed: Aim 1. To test the hypothesis that M3R modulates the function of olfactory sensory neurons Aim 2. To test the hypothesis that M3R is involved in odor-mediated activation of alternative signaling Aim 3. To identify structural domains of M3R and signaling components important for the functional interaction of M3R and OR The proposed experiments further our long term goal, which is to understand the mechanistic basis for regulation of odorant receptor function. The health relatedness of these studies is that a better understanding of the regulatory mechanism of ORs and downstream signal transduction will offer insights into the general features of signaling by GPCRs, the most frequent pharmaceutical targets for cardiac, psychiatric, and cancer diseases. This work will advance our understanding on how G protein-coupled ORs are regulated by another GPCR, M3R, which is activated by acetylcholine, the key neurotransmitter of the parasympathetic nervous system. An understanding of the interactions between the neurotransmitter receptor and the peripheral olfactory system provides crucial information that may contribute toward novel therapy for anosmic and hyposmic patients who have compromised sense of smell, and to reduce stress associated with malodor, improving their quality of life. PUBLIC HEALTH RELEVANCE: The health relatedness of these studies is that a better understanding of the regulatory mechanism of ORs and downstream signal transduction will offer insights into the general features of signaling by GPCRs, the most frequent pharmaceutical targets for cardiac, psychiatric, and cancer diseases. This work will advance our understanding on how G protein- coupled ORs are regulated by another GPCR, M3-R, which is activated by acetylcholine, the key neurotransmitter of the parasympathetic nervous system. An understanding of the interactions between the neurotransmitter receptor and the peripheral olfactory system provides crucial information that may contribute toward novel therapy for anosmic and hyposmic patients who have compromised sense of smell, and to reduce stress associated with malodor, improving their quality of life.